A spinal mechanism of action is involved in the antinociception produced by the capsaicin analogue NE 19550 (olvanil).
We have studied the effect of NE 19550 (olvanil, N-(4-hydroxy-3-methoxyphenyl) methyl-9Z-octadecenamide), a capsaicin analogue with approximately equipotent antinociceptive activity in vivo compared with capsaicin, on nociceptive responses recorded from spinal dorsal horn neurones in vivo and from a spinal ventral root in vitro. In adult rats anaesthetized with halothane, antinociceptive doses of olvanil (20-40 mumol/kg, s.c.) reduced C-fibre responses evoked in wide dynamic range, lumbar dorsal horn neurones, by peripheral transcutaneous electrical stimulation. Intradermal injection of olvanil, localized to a discrete region of the peripheral receptive field, did not activate C-fibres nor change C-fibre evoked activation of dorsal horn neurones. Spinal intrathecal administration of olvanil attenuated C-fibre evoked responses and, at the highest concentration, significantly reduced A beta-fibre evoked activity. In the neonatal rat spinal cord/tail preparation maintained in vitro, superfusion of the cord with olvanil (500 nM-5 microM) did not evoke a depolarization but responses to peripheral noxious stimulation were attenuated. In a similar in vitro preparation of the neonatal rat spinal cord, the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) was measured in spinal cord superfusates. Capsaicin (2-10 microM) evoked a large release of CGRP-LI but olvanil (2-10 microM) produced only a small or undetectable release. Following the administration of each substance, however, the release of CGRP-LI evoked by a depolarizing potassium stimulus was significantly attenuated. These data indicate that C-fibre input to the dorsal horn was attenuated by acute systemic doses of olvanil that were antinociceptive in behavioural tests. This effect was unlikely to be due to impairment of C-fibre function by a peripheral locus of action but was more consistent with an action in the spinal cord in which the reduced release of a neurotransmitter substance from afferent nerve terminals may play a prominent role.
Dickenson
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Sandoz Institute for Medical Research, 5 Gower Place, LondonU.K. Department of Pharmacology, University College, LondonU.K.
Hughes
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Rueff
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Dray
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007271:Injections, Intradermal; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D009619:Nociceptors / Q000187:drug effects*; D010477:Perfusion; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C054256:olvanil; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin